Reagent component dispensing caps for reagent containers used in automated clinical analyzers

ABSTRACT

Described is an automated reagent dispensing cap and methods of use in an automated clinical analyzer for introducing one or more reagent components housed in the reagent dispensing cap into a container enclosing another reagent component with which it is combined to achieve a reagent useful for diagnostic testing.

TECHNICAL FIELD OF THE INVENTION

The present invention is related to in-vitro diagnostic (IVD) testingprocedures. More specifically, the present invention provides reagentcomponent dispensing caps for reagent containers for storing and mixingreagent components of reagents used in diagnostic tests and conducted inan automated clinical analyzer. The present invention also providesmethods of use of the reagent dispensing caps.

BACKGROUND

Currently available in-vitro diagnostic (IVD) testing procedures areencumbered with numerous steps that involve manual interventions beforea reagent can be prepared for use in a liquid and/or powder format. Forinstance, in a diagnostic testing lab, before using the reagents forsample testing, typically patient body fluids such as whole blood,plasma, serum, urine, cerebrospinal fluid and the like, a medical workercollects different reagent components from separate vials/bottles, usesa pipette to pipette diluents with a certain volume to the vial ofpowdered reagents or to the vial with concentrated liquid reagents,waits for a certain time for reconstitution, and finally mixes thereagents manually by shaking, stirring, or rotating, for example. Thismanual process reduces the speed in which a diagnostic test iscompleted, increases the risk of human error and operator contaminationwith potentially toxic chemicals, and raises the cost of packaging.

In addition to the above mentioned drawbacks in the preparation of thereagents, the reagent components in a reagent container (e.g., a vial ora bottle) are susceptible to evaporation when the reagent container isplaced in a clinical analyzer. Evaporation of reagent(s) compromise theconsistency of the reagent's stability and wastes reagents. Moreimportantly, evaporation of reagents compromises the consistency inresults generated by the clinical analyzer and the results areunreliable. Therefore, there is a need to improve on reagent containersfor storing and mixing components of reagents for use in diagnostictests that are conducted in an automated clinical analyzer. There isalso a need to improve on the reagent preparation process and to improveon the usage efficiency of the reagent containers for IVD applicationsin an automated clinical analyzer. A reagent packaging solution thataddresses these disadvantages is described below.

SUMMARY OF INVENTION

Described herein is a reagent packaging solution with multi-componentstorage, automated reconstitution and mixing of the stored components,and evaporation prevention of the stored components.

In one aspect, the invention is directed to a device for storing anddispensing reagent components in an automated clinical analyzer. Thedevice according to this aspect of the invention comprises a housinghaving a first end and an adjacent first opening, a second end and anadjacent second opening, and internal threads extending along at least aportion of an internal surface of the housing. The housing defines achamber with a lumen positioned between the housing first and secondends. A cylindrical member positioned at the first end of the housingcomprises a first end and a second end. The cylindrical member hasexternal threads for mating with at least the internal threads of thehousing. The cylindrical member is rotatable on the internal threads ofthe housing and translatable from the first end of the housing towardsthe second end of said housing. In one embodiment of this aspect of theinvention, a seal is positioned across the lumen of the second end ofthe chamber between the second end of the housing and the second end ofthe cylindrical member.

In one embodiment of this aspect of the invention, the device includes areagent component positioned in the lumen of the chamber between theseal and the second end of the cylindrical member. In one embodiment, anactuator is operably positioned at the first end of the cylindricalmember. The actuator may feature a ram, a needle, or the rotatablecylindrical member.

In various embodiments of this aspect of the invention, the deviceincludes a seal that may be integral with and joined to the second endof the cylindrical member. An attachment piece may be positioned at thesecond end of the housing for mating to a container. The attachmentpiece in various embodiments may consist of threads, snap-lock, matingrings, receiving grooves, a friction-fit mechanism, Luer lock, or one ormore tabs. A plurality of external threads for mating with the containermay be positioned on the external surface of the first end of thehousing. The device may further feature a cap for reversibly sealing thefirst opening of the housing.

In another aspect, the invention is directed to a device for storing anddispensing reagents, comprising a housing having a long axis, a firstend, and an adjacent first opening, and a second end and an adjacentsecond opening. The housing defines a chamber having a lumen positionedbetween the first and second ends, and a deformable member positionedacross the lumen of the chamber. The deformable member includes apiercing probe including a pointed tip positioned on the side of thedeformable membrane that is closest to the second end of the housing. Inthis aspect of the invention, a seal for sealing the lumen of thechamber is positioned in the lumen of the chamber between the second endof the housing and the tip of the piercing probe. A chamber for storingreagents is positioned between the seal and the deformable member. Thedevice according to this aspect of the invention includes an attachmentpiece at the second end of said housing for mating to a container. Theattachment piece may be a snap-lock mechanism, friction-fit mechanism,threads, one or more tabs, receiving grooves, mating rings, and a Luerlock, or one or more grooves. The device according to this aspect of theinvention may further feature a cap for reversibly sealing the firstopening of the housing and a ram for actuating the device.

In another aspect the invention is directed to a device for storing anddispensing reagents, comprising a cylindrical housing as described aboveand a plug positioned and laterally slideable in the lumen of thechamber. The plug defines a through hole in the plug that is parallel tothe long axis of the housing. The through hole includes a reservoir forstoring a substance such as a reagent component. The substance isreleased from the reservoir when the through hole is aligned with thelumen of the chamber. The device according to this aspect of theinvention includes an attachment piece at the second end of the housingfor mating to a container. The attachment piece in various embodimentsis a snap-lock mechanism, friction-fit mechanism, threads, one or moretabs, receiving grooves, mating rings, a Luer lock, or one or more tabs.

In another aspect, the invention is directed to a method for storingreagent components in a reagent dispensing cap and automated mixing ofreagent components to prepare a diagnostic reagent in an automatedclinical analyzer according to the various embodiments of the devicedescribed herein.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1A illustrates a longitudinal transverse section of an exemplaryreagent dispensing cap releasably joined to a container according to anembodiment of the invention;

FIG. 1B illustrates a transverse section of an exploded view of thehousing and cylindrical member of the reagent dispensing cap illustratedin FIG. 1A according to an embodiment of the invention;

FIG. 1C illustrates a partial transverse section of the housing of thereagent dispensing cap illustrated in FIG. 1A including an exemplaryseal joined to the top portion of a container according to an embodimentof the invention;

FIG. 2A illustrates a partial transverse section of an exemplary reagentdispensing cap illustrating a first reagent component disposed in achamber located between the second end of the cylindrical member and aseal according to an embodiment of the invention;

FIG. 2B illustrates a partial transverse section of an exemplary reagentdispensing cap illustrating a blister pack holding a first reagentcomponent disposed in a chamber located between the second end of thecylindrical member and a seal according to an embodiment of theinvention;

FIG. 2C illustrates a partial transverse section of an exemplary reagentdispensing cap with the first reagent component distributed on the endof the cylindrical member according to an embodiment of the invention;

FIG. 3A is a transverse section of a reagent dispensing cap according tothe invention illustrating axial rotation of the cylindrical membertowards the first reagent component housed between the seal and thesecond end of the cylindrical member illustrated in FIG. 1A by a ramapplied to the first end of the cylindrical member according to anembodiment of the invention;

FIG. 3B illustrates a partial transverse section of an exemplary reagentdispensing cap illustrating a first reagent component disposed in achamber located between a deformable membrane including a needle, and aseal according to an embodiment of the invention;

FIG. 4A illustrates a transverse section of an exemplary reagentdispensing cap including a needle axially positioned at the second endof the cylindrical member according to an embodiment of the invention;

FIG. 4B is a partial transverse section of a reagent dispensing capaccording to the invention illustrating axial rotation of thecylindrical member towards the first reagent component housed betweenthe seal and the second end of the cylindrical member illustrated inFIG. 4A by a ram applied to the first end of the cylindrical memberaccording to an embodiment of the invention;

FIG. 5A illustrates another embodiment of the reagent dispensing capaccording to the invention including a threadless housing and athreadless cylindrical member;

FIG. 5B illustrates actuation of the reagent dispensing cap illustratedin FIG. 5A to dispense the first reagent component into the container byapplication of a ram to the first end of the cylindrical member to pushthe opposite end of the cylindrical member into the lumen of theattached container;

FIG. 6A illustrates yet another embodiment of the reagent dispensing capaccording to the invention in which the housing includes a slider;

FIG. 6B illustrates actuation of the slider illustrated in FIG. 6A forreleasing a first reagent component into the lumen of the attachedcontainer.

DESCRIPTION

Described below is an automated reagent dispensing cap for separatelystoring and automatically dispensing at least one stored component to becombined with another stored component to make a reagent used indiagnostic assays, and methods for dispensing the stored component whenused in an automated clinical analyzer, including hemostasis analyzers,immunoassay analyzers, chemistry analyzers, and the like. The storedreagent component(s) (i.e., one or more of the reagent components) ishoused in the reagent dispensing cap freely, or in a primary pack suchas a pouch, blister pack, pill, bag, using a membrane (e.g., apierceable membrane) or in an ampoule containing one or more reagentcomponents. The stored reagent components can be in a liquid form (e.g.,a concentrate), a gel form or in the form of a dry component, e.g.,powder, tablet, lyophilized, or granulated format.

The stored reagent component(s) in the reagent dispensing cap accordingto the invention are stored in a manner that prevents oxygen or moisturefrom influencing the chemical or the physical properties of the storedreagent component(s). In one embodiment, a seal cap is provided on oneend of the cap to minimize contact between the reagent component(s)stored in the cap and the external environment surrounding the cap.Storage of the reagent component(s) in this manner minimizes loss of thereagent component(s) through evaporation.

The reagent dispensing cap according to the invention is disposed on acontainer which houses a second reagent component in the form of aliquid, gel or a dry component, e.g., powder, tablet, lyophilized, orgranulated format. The contents of the reagent dispensing cap aredispensed into the container to which it is joined by an openingmechanism such as, but not limited to rotating or pushing the cap or aportion of the cap actuated by a plunger such as a ram, to break a seal,such as an elastomeric membrane, between the dispensing cap andcontainer to release the stored component from the cap into thecontainer to which it is joined. Various combinations and arrangementsof components in the reagent dispensing cap and components in acontainer with which the reagent cap component will be mixed arecontemplated by the invention.

These and other objects, along with advantages and features of thepresent invention described herein, will become apparent throughreferences to the following description and the claims. Furthermore, itis to be understood that the features of the various componentsdescribed herein are not mutually exclusive and can exist in variouscombinations and permutations.

In one aspect, the invention is directed to a device for storage of andautomated dispensing of at least one reagent into a container to becombined with another component in the container to make a diagnosticreagent for use in an automated clinical analyzer, for example,Hemostasis Analyzer, ACLTOP® (Instrumentation Laboratory Company,Bedford, Mass.).

Referring to FIGS. 1A-C, an automated reagent dispensing cap 10according to the invention includes a cylindrical housing 12 having afirst end 20 and an adjacent first opening 21, a second end 22, and anadjacent second opening 23. The housing 12 defines a chamber 62 with alumen 24 between the first end 20 and second end 22. The chamber 62 mayextend from the first end 20 to the second end 22 of the housing 12 ormay be confined toward the second end 22 of the housing 12 as describedin greater detail below. In one embodiment of the invention, a seal cap100 is positioned on the first end 20 of the housing 12.

In one embodiment according to the invention, the chamber 62 stores afirst reagent component that when mixed with a second reagentcomponent(s) stored in a joined container 72 forms a reagent for adiagnostic assay. The housing 12 further includes internal threads 30which extend along the interior wall of the housing, preferably but notlimited to extending from the first end 20 to the second end 22 of thehousing 10.

With continued reference to FIGS. 1A and 1B, in one embodiment of theinvention, the reagent dispensing cap 10 further includes a cylindricalmember 40 having a long axis and a first end 42 near the first opening21 of the housing 12 and a second end 44 opposite to the first end 42.The cylindrical member 40 is positioned within the lumen 24 and orientedalong the long axis of the housing 12. The cylindrical member 40includes external threads 50 that are arranged to mate with the internalthreads 30 of the housing 12. The cylindrical member 40 is rotatable onor around the internal threads 30 of the housing 12. The mating of theexternal threads 50 of the cylindrical member 40 with the threads 30 ofthe housing 12 prevents the reagent contents in the cap 10 from exposureto external elements, such as moisture or oxygen, as well as preventingevaporation of the reagent contents in the housing 12.

Referring to FIGS. 1A-C, the seal cap 100 additionally prevents orminimizes the reagent component(s) in chamber 62 from coming in contactwith oxygen or moisture in an external environment surrounding the cap10. The seal cap 100 also minimizes evaporation of the reagentcomponent(s) in the reagent dispensing cap 10.

As shown in FIG. 1C, in one embodiment of the invention, the reagentdispensing cap 10 further includes a seal 60, such as a frangiblemembrane positioned at the second end 22 of the chamber 62 of thecylindrical housing 12. The seal 60 prevents the contents of the chamber62 from mixing with the second reagent component(s) stored in the joinedcontainer 72. The space between the second end 44 of the cylindricalmember 40 and the seal 60 defines the boundary of the chamber 62 in thisembodiment.

As shown in FIG. 2A, in one embodiment, the chamber 62 houses a freelydisposed liquid or powdered first component of a reagent. Alternatively,referring now to FIG. 2B, the chamber 62 houses a packet 64 such as apack, for example a blister pack or ampoule that contains the firstreagent component. Alternatively, illustrated in FIG. 2C, the firstreagent component is distributed on the second end 44 of the cylindricalmember 40, for example, by coating the surface of the second end 44, orenclosing a reagent component in foil 43 joined to the second end 44 ofthe cylindrical member 40.

Referring to FIGS. 3A and 3B, in other embodiments one or more reagentcomponents is distributed in a packet, e.g., a pouch, pill, or bag inthe reagent dispensing cap. In the event that the one or more reagentcomponents are stored in a packet, the packet may be ruptured by apiston, e.g., the cylindrical member 40, a piercing probe 74 (e.g., aneedle), or by twisting of the reagent dispensing cap 10 (e.g.,rotational movement of the cap 10), discussed in greater detail below.

Referring now to FIG. 3A, in one embodiment of the invention, thecylindrical member 40 of the reagent dispensing cap 10 is actuated torotate axially toward a container 72 to which it is joined, via themated external threads 50 of the cylindrical member and the internalthreads 30 of the housing 12 by applying a ram 70 to the first end 42 ofthe cylindrical member 40. The cylindrical member 40, as illustrated inFIG. 3A, compresses the contents of the chamber 62 thereby rupturing theseal 60 to release the contents of the chamber 62 into the container 72where it contacts a second reagent component.

Alternatively, referring to FIG. 3B, chamber 62 for storing a reagentcomponent is bounded by a deformable diaphragm 80 on the side of thechamber 62 towards the second end 44 of the cylindrical member 40 and bythe seal 60, e.g., a pierceable membrane on the opposite side of thechamber 62. In one embodiment of the invention, the deformable diaphragm80 includes a piercing probe 74 comprising a sharp pointed tip (e.g., aneedle) that extends axially towards the seal 60.

In one embodiment of the invention illustrated in FIGS. 4A and 4B, thecylindrical member 40 includes a piercing probe 74 comprising a sharppointed tip, for example, a needle, axially disposed at the second end44 of the cylindrical member 40. As the cylindrical member 40 is rotatedby the ram 70 towards the seal 60, best illustrated in FIG. 4B, the seal60, or a packet, e.g., a blister pack or pouch 64 is pierced and itscontents released into the container 72 where it is contacted with thesecond reagent component housed in the container 72.

In yet another embodiment of the reagent dispensing cap 10, referring toFIGS. 5A and 5B, the housing 12 and the cylindrical member 40 are freeof threads. In this embodiment, the cylindrical member 40 includes anintegral chamber 80 at a portion of the second end 22 of the housing 12.The integral chamber 80 houses the first reagent component. A seal 60 isdisposed on the container side of the chamber 80 at the second end 22 ofthe housing 12. A ram 70 is applied to the first end 42 of thecylindrical member 40 and axially pushes the cylindrical member 40axially towards the container 72 until the seal 60 of the chamber 80 isintroduced into the lumen of the container 72 wherein the contents ofthe chamber 80 are released and placed in contact with the contents ofthe container 72.

FIG. 6A-6B illustrates an embodiment of the reagent dispensing cap 10absent a cylindrical member. Referring to FIG. 6A, reagent dispensingcap 10 in this embodiment, includes a housing 12 with a central axiallydisposed lumen 11. The housing 12 includes a slider 9, for example, aslideable plug that is capable of moving laterally (arrow 7), i.e., in adirection that is perpendicular to the lumen 11 of the housing 12. Theslider 9 may be disc-shaped, rectangular or cylindrical, for example.The slider 9 includes one or more through-holes such as a chamber 5 forhousing a reagent component in the reagent dispensing cap 10. Thechamber 5 is open on the end of the chamber 5 that faces a container 72that joins to the reagent dispensing cap 10. Referring to FIG. 6B, thechamber 5 is slideable laterally into the lumen 11 of the housing 12when the slider 9 is pushed or pulled laterally by an actuator (notshown) in the clinical analyzer. When the chamber 5 is positioned in thelumen 11, the reagent component housed in chamber 5 is released into thecontainer 72 that is joined to the reagent dispensing cap 10 asillustrated in FIG. 6B.

The reagent dispensing cap 10 is reversibly attachable to the container72. For example, referring again to FIGS. 1A and 1B, the second end 22of the housing 12 of the reagent dispensing cap 10 includes anattachment device 75 for joining the reagent dispensing cap 10 to thecontainer 72. The attachment piece 75 may be, for example, internalthreads on the second end 22 of the housing 12 that mate with externalthreads on the open end of the container, or a snap-lock, receivinggrooves, a friction fit, a Luer lock, or one or more tabs.

A tamper-preventive tear-strip 76, for example, as illustrated in FIG.5A, may be positioned between the reagent dispensing cap 10 andcontainer 72 to prevent inadvertent activation of the reagent dispensingcap 10.

The present invention provides the advantage of having multi-componentreagent storage utilizing a section in the cap 10, e.g., the housing 12,to independently store one or more reagent components in liquid or dryform without exposing the reagent components to moisture or to oxygenthat would otherwise alter their chemical or physical properties, orboth, and without mixing the reagent components in the cap 10 with thereagent components in the joined container 72. Mixing the stored reagentcomponents in the cap 10 with the reagent components in the joinedcontainer 72 when needed provides the additional benefit of reliableresults because the reagent components were not pre-mixed and thenstored for a longer period of time that would result in reagentdeterioration.

Storage of one or more reagent components in a section of the cap 10,e.g., the housing 12, prior to its automated dispensing into the joinedcontainer 72 minimizes evaporation of the components in the housing 10and in the joined container 72. Accidental human intervention isminimized because the release and the mixing of reagent componentsseparately stored in the housing 12 and the container 72 is automated.The invention described herein minimizes errors in analytical resultscaused by prolonged storage and degradation of a prepared reagent, andthe accidental loss of reagent components caused by human intervention.These features add to the cost-effectiveness of the reagents and theanalysis of a patient sample.

EXEMPLIFICATIONS

An Exemplary Dual Chamber Reagent Mixing Container for HemostasisTesting in an Automated Clinical Hemostasis Analyzer Instrument

A specific non-limiting example of the reagent dispensing cap accordingto the invention described above is a reagent dispensing cap forprothrombin time (PT) testing by an automated hemostasis analyzerinstrument. The reagent for PT testing contains two components: adiluent and a concentrated PT reagent. The volume ratio between thediluent and the PT reagent is 19:1. Each PT test requires 100l dilutedPT reagent. A reagent dispensing cap useful for PT tests in an automatedclinical analyzer would generally require between about 500 to about1000 PT tests. A 1000 PT test reagent dispensing cap requires about 100ml of diluted PT reagent, namely 95 ml diluent and 5 ml concentrated PTreagent. In the exemplary reagent cap disclosed herein, for example thereagent cap and container illustrated in FIG. 1, the container 72 intowhich the reagent dispensing cap empties would have a volume capacitygreater than 100 ml and would initially contain 95 ml of diluent. Thechamber of the reagent cap would contain 5 ml of concentrated PTreagent. Upon actuation by the cylindrical member described in the aboveembodiments, the 5 ml of concentrated PT reagent is introduced into thecontainer and contacts the second reagent component held in thecontainer 72. A self-contained PT reagent dispensing cap 10 withautomated reagent preparation, sustainable for about 1000 PT assays, istherefore achieved.

An Exemplary Dual Chamber Reagent Mixing Container for Analyte Testingin an Automated Clinical Analyzer

A second non-limiting example of the reagent dispensing cap according tothe invention is a dispensing cap for a hemostasis quality control (QC)reagent, for example. A specifically prepared, lyophilized plasma samplewith known analytical testing results would serve as a QC reagent. TheQC reagent is stored in the container to which the reagent dispensingcap is joined. De-ionized water is stored in the chamber of the reagentdispensing cap. Prior to use, the deionized water is introduced from thechamber in the reagent dispensing cap into the container holding thelyophilized QC reagent.

What is claimed is:
 1. A device for storing reagent components in anautomated clinical analyzer, comprising: a container lid, said containerlid comprising, a cylindrical wall about a longitudinal central axis,the cylindrical wall defining a lumen, a first opening to the lumen at afirst end of the cylindrical wall, a second opening to the lumen at asecond end of the cylindrical wall a portion of the lumen defining areagent chamber 62 configured to store one or more reagents, wherein thecylindrical wall further comprises internal threads 30 extending fromthe first end 20 to the second end 22 of the cylindrical wall; acylindrical member 40 positioned within the lumen and confined betweenand shorter than the distance between the first and second ends, saidcylindrical member 40 comprising external threads 50 configured tooperatively engage the internal threads 30 of said cylindrical wall andthereby to move the cylindrical member along the central longitudinalaxis within the lumen, and wherein said engagement between the internalthreads 30 and said external threads 50 form a gas-tight seal betweenthe first opening of the lumen and the reagent chamber 62; a breakableseal 60 positioned at the second end 22 of cylindrical wall extendingacross the second opening of the lumen, wherein the reagent chamber 62is bounded by the cylindrical wall, the cylindrical member 40 and thebreakable seal 60; and an attachment structure 75 joined to the secondend of the cylindrical wall, the attachment structure 75 including anengagement portion shaped for receiving a mating engagement portion of acontainer 72 at an opening of the container 72 and retaining thecylindrical wall and the breakable seal 60 in a fixed position againstthe container 72 such that the breakable seal 60 seals the opening ofthe container
 72. 2. The device of claim 1, wherein said attachmentstructure 75 is selected from the group consisting of threads,snap-lock, mating rings, receiving grooves, a friction-fit mechanism,Luer lock, and one or more tabs.
 3. The device of claim 1, furthercomprising; a cap 100 positioned at the first end 20 of the cylindricalwall, the cap 100 enclosing the cylindrical member and sealing the firstopening of the lumen.
 4. The device of claim 3, wherein said cap 10 isconfigured to reversibly attach to the container
 72. 5. The device ofclaim 1, further comprising; the container 72 coupled to the containerlid via the attachment structure
 75. 6. The device of claim 5, furthercomprising: a first reagent stored in the reagent chamber of thecontainer lid; and a second reagent separately stored in the container,wherein the first reagent and the second reagent are separated from eachother by the breakable seal
 60. 7. The device of claim 6, wherein thefirst reagent is capable of breaking the breakable seal and mixing withthe second reagent in response to displacement of the cylindrical memberalong the longitudinal axis toward the breakable seal.
 8. The device ofclaim 1, further comprising a piercing probe extending from thecylindrical member toward the breakable seal, the piercing probeincluding a pointed tip configured for piercing the breakable seal inresponse to displacement of the cylindrical member along thelongitudinal axis toward the breakable seal.